The binding of NK cells to lysis-sensitive (LS) target cells initiates a series of biochemical responses. Although most of the initiated pathways appear to participate during NK cell effector function, the induction of elevated cAMP levels may elicit a feedback regulatory system. This proposal seeks to further define how LS-target cell binding induces increased cellular accumulation of cAMP, and how this impacts upon NK cell effector capabilities. This proposal is divided into four specific aims, with the first three committed to understanding the mechanisms involved with elevating cAMP levels. The first aim will characterize the relative contributions of increased adenylyl cyclase (AC) and decreased phosphodiesterase (PDE) activities to this increase. The second aim will determine how receptor occupancy regulates AC activity. The third aim is to identify which PDE isoforms are operative in NK cells and how their activities are regulated after engagement of LS-targets. The fourth aim will initiate the characterization of how elevated cAMP levels impact on the cytolytic capabilities of NK cells.